Mechanism of HIF-1α-mediated angiogenesis in rheumatoid arthritis and progress of natural medicine interventions.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by hyperplasia of synovial pannus and progressive joint destruction. Pathological angiogenesis, driven by hypoxia-inducible factor-1α (HIF-1α), constitutes a core pathological mechanism and has become a critical therapeutic target for RA. This article systematically elucidates the molecular mechanisms by which HIF-1α drives pathological angiogenesis through interactions with signaling pathways such as vascular endothelial growth factor (VEGF), angiogenin (ANG)-1/2, CXC chemokine ligand 12 (CXCL12)/CXC chemokine receptor 4 (CXCR4), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR). HIF-1α-mediated angiogenesis forms a positive feedback network with pathological processes including synovial inflammatory response, glycolytic metabolic reprogramming, and oxidative stress-mitochondrial damage, collectively promoting synovial pannus formation. Additionally, this article summarizes the effects of traditional Chinese medicine formulations and plant-derived monomeric metabolites on HIF-1α-mediated RA synovial angiogenesis, as well as the preclinical research advances of anti-angiogenic mechanisms. It also briefly explores the potential of novel botanical drugs delivery systems in enhancing the targeting of natural products to the HIF-1α pathway and improving therapeutic efficacy, aiming to provide new perspectives and strategic options for HIF-1α-targeted RA therapies.